Cell proliferation occurs in response to various stimuli and may stem from de-regulation of the cell division cycle (or cell cycle), the process by which cells multiply and divide. Hyperproliferative disease states, including cancer, are characterized by cells rampantly winding through the cell cycle with uncontrolled vigor due to, for example, damage to the genes that directly or indirectly regulate progression through the cycle. Thus, agents that modulate the cell cycle, and thus hyperproliferation, could be used to treat various disease states associated with uncontrolled or unwanted cell proliferation.
Mechanisms of cell proliferation are under active investigation at cellular and molecular levels. At the cellular level, de-regulation of signaling pathways, loss of cell cycle controls, unbridled angiogenesis or stimulation of inflammatory pathways are under scrutiny, while at the molecular level, these processes are modulated by various proteins, among which protein kinases are prominent suspects. Overall abatement of proliferation may also result from programmed cell death, or apoptosis, which is also regulated via multiple pathways, some involving proteolytic enzyme proteins. Among the candidate regulatory proteins, protein kinases are a family of enzymes that catalyze phosphorylation of the hydroxyl group of specific tyrosine, serine or threonine residues in proteins. Typically, such phosphorylation dramatically perturbs the function of the protein, and thus protein kinases are pivotal in the regulation of a wide variety of cellular processes. For example, without wishing to be bound to a particular theory, it is believed that as inhibitors of protein kinases, such as, for example, cyclin dependent kinases (“CDK”), the inventive agents can modulate the level of cellular RNA and DNA synthesis and therefore are expected to be useful in the treatment of viral infections such as HIV, human papilloma virus, herpesvirus, Epstein-Barr virus, adenovirus, Sindbis virus, poxvirus and the like. (See Schang, et al, J. Virol. 74, 2107–2120 (2000)). Additionally, CDK5 has been implicated in the phosphorylation of tau protein, suggesting potential methods of treating or preventing Alzheimer's disease (Hosoi, et al, J. Biochem. (Tokyo), 117, 741–749 (1995)). CDKs are serine-threonine protein kinases that play critical roles in regulating the transitions between different phases of the cell-cycle, such as the progression from a quiescent stage in G1 (the gap between mitosis and the onset of DNA replication for a new round of cell division) to S (the period of active DNA synthesis), or the progression from G2 to M phase, in which active mitosis and cell-division occurs. CDK complexes are formed through association of a regulatory cyclin subunit (e.g., cyclin A, B1, B2, D1, D2, D3, and E) and a catalytic kinase subunit (e.g., CDK1, CDK2, CDK4, CDK5, and CDK6). As the name implies, the CDKs display an absolute dependence on the cyclin subunit in order to phosphorylate their target substrates, and different kinase/cyclin pairs function to regulate progression through specific phases of the cell-cycle.
A number of indazole derivatives have thus far been identified to have therapeutic potential: GB 2345486 discloses indazole derivatives as tyrosine kinase inhibitors, EP0518805 identifies indazoles substituted with piperidines having sigma receptor activity; WO 89/43969 discloses indazoles of cyclic ureas useful as HIV protease inhibitors; U.S. Pat. No. 4,415,569 identifies pyrazoloindazole derivatives having bronchodilating action; U.S. Pat. No. 5,208,248 discloses indazoles for the treatment of migraines. Other therapeutic applications for indazole derivatives are discussed in WO 96/20192, EP 04994774, JP 60/004184, EP0023633, U.S. Pat. No. 4,051,145, JP59/228248, GB 1/376600, U.S. Pat. No. 4,978,603, EP0904769 and in the literature by De Lucca et al, Journal of Medicinal Chemistry, 42, 135–52 (1999). General synthetic schemes for the preparation of indazole derivatives are disclosed Wentrup et al, Journal of Organic Chemistry, 43, 203–741(1978); Fugimura et al, Chemical Abbstracts, 1070, 749 (1987). More particularly, 3,5 substituted indazoles have been identified as protein kinase inhibitors: WIPO International Publication No. 01/85726 discloses indazole compounds substituted with 1,1-dioxoisothiazolidine as CDK inhibitors; WO 02/10137 discloses 3,5 substituted indazoles as inhibitors of Jun N-terminal kinase inhibitors; and U.S. Pat. No. 6,555,539 and WO 03/004488 discloses 3,5 substituted indazoles with a benzimidazole in the 3-position.
There is still a need, however, for more potent inhibitors of CDK and in particular, for CDK inhibitors which possess both high affinity for the target CDK kinase as well as high selectivity versus other protein kinases. The inventive compounds are generally more selective for CDK inhibitors than the compounds described in previous publications.